PROJECT SUMMARY Prescription opioid use in pregnancy has increased dramatically over the past two decades. Yet, few studies have examined the impact of opioids used for pain on adverse pregnancy outcomes. Some data suggest that prenatal opioid analgesics may be associated with a higher risk of certain birth defects. However, evidence is limited by discrepant study results, poor maternal recall of medication use, and small sample sizes. In addition to these concerns, there are little data on the risk of preterm and small for gestational age birth following opioid analgesic exposure, and stillbirth has not been studied. Evidence of the safe use of prenatal opioid analgesics is thus inconclusive. The primary goal of this study is to determine the risks associated with exposure to opioids for pain in pregnancy independent of biases that have affected prior studies. We will examine several important adverse pregnancy outcomes possibly associated with such exposure including specific birth defects, preterm birth, small for gestational age birth, and stillbirth. The outcomes of maternal and infant opioid dependence following prenatal opioid analgesic exposure also will be evaluated. To achieve this goal we have assembled a population-based cohort of all pregnancies in Ontario, Canada (N?790,000) from 2012-2017, 30,262 of which were exposed to opioid analgesics during pregnancy. Using modern methods such as high-dimensional propensity score adjustment and sensitivity analyses of alternative referents (including infants unexposed to opioid analgesics and infants unexposed to opioid analgesics but prenatally exposed to other analgesics), we will determine the associations between particular opioid analgesic exposures during the etiologically relevant windows of gestation and these maternal and infant outcomes. This will be the first study to examine the duration and dose of prenatal analgesic opioids on the risk of these adverse outcomes. Our population-based cohort study will provide estimates of the absolute risk of these outcomes, which cannot be estimated from existing US case-control studies, and which are needed to inform maternal treatment choices. Studies of the safety of prenatal medications in extant US data such as Medicaid exclude 80% of pregnancies (i.e., women with restricted benefits, capitated care, private insurance, or incomplete enrollment during pregnancy) to have complete pregnancy data, which may result in selection bias or results that cannot be generalized. Concerns of generalizability also apply to US private insurance beneficiaries. To overcome these limitations we propose a population-based cohort study using an extant database of universal healthcare coverage and complete prescription data for Ontario, Canada?s most populous province of 13 million. Clinical care and characteristics of pregnant women in the US and Canada are similar, thus the results of this study will have direct relevance for US providers and pregnant women. Better understanding of the risks of prenatal opioid analgesics will direct treatment of pain in pregnancy and management of exposed infants.